Case Report: Ursodeoxycholic acid treatment in Niemann-Pick disease type C; clinical experience in four cases

Abstract

In this case series, we demonstrate that Ursodeoxycholic acid (UDCA) improves liver dysfunction in Niemann-Pick type C (NPC) and may restore a suppressed cytochrome p450 system. NPC disease is a progressive neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Liver disease is a common feature presenting either acutely as cholestatic jaundice in the neonatal period, or in later life as elevated liver enzymes indicative of liver dysfunction. Recently, an imbalance in bile acid synthesis in a mouse model of NPC disease was linked to suppression of the P450 detoxification system and was corrected by UDCA treatment. UDCA (3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, is used to treat various cholestatic disorders. In this report we summarise the findings from four independent cases of NPC, three with abnormal liver enzyme levels at baseline, that were subsequently treated with UDCA. The patients differed in age and clinical features, they all tolerated the drug well, and in those with abnormal liver function, there were significant improvements in their liver enzyme parameters.

Current Challenges in Understanding the Cellular and Molecular Mechanisms in Niemann–Pick Disease Type C1

“…Another treatment approach is the application of arimoclomol, a coinducer of heat shock protein 70 (HSP 70) that improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro [62,63]. Beneficial effects for NPC patients have also been observed with drugs such as ursodeoxycholic acid [64,65] and acetyl-DL-leucine [66].…”

Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C

“…In another study (complementary to the murine work detailed here), UDCA was trialed in four clinical NPC cases with improvements in liver function (including reduced aspartate aminotransferase (AST) and alanine transaminase (ALT)) in those patients with elevated liver enzymes at baseline 12 .…”

“…When four NPC1 patients were treated with UDCA, benefit was observed based on improved liver function 12 . Very interestingly, one patient was switched from UDCA to CA and their clinical status declined but was recovered upon switching back to UDCA.…”

Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C

“…The expression of the P450 system genes could be rescued in Npc1 -/- mice by administering the bile acid UDCA, leading to clinical benefit 3 . In another study, UDCA was trialed in four clinical NPC cases and liver function improved in patients with elevated liver enzymes at baseline 10 .…”

“…When four NPC1 patients were treated with UDCA, benefit was observed based on improved liver function 10 . Very interestingly, one patient was switched from UDCA to CA and their clinical status declined but was recovered on switching back to UDCA, and this has striking parallels with this study in mice.…”